Synaptic transmission is the major cellular process used for intercellular communication between neurons in the brain. In the last several years many of the proteins important in mediating neurotransmitter release have been identified and functional studies have led to a series of proposals for the biochemical pathway of vesicle docking, activation and release. In spite of this progress, many critical events in membrane trafficking within the nerve terminal are not understood and the roles of many proteins remain to be determined. Two recently identified mammalian proteins, rsec6 and rsec8, share sequence homology =with yeast genes important for secretion. This proposal will investigate the potential roles of these molecules in presynaptic transmitter release. We will test the specific hypothesis that the rsec6 and rsec8 molecules function in conjunction with a low-molecular weight GTPase, or Rab protein, to regulate early aspects of vesicle docking. Further, we propose to study the localization of the rsec6 and rsec8 molecules and to characterize their biochemical interactions with other components of the secretory pathway. These studies are expected to further elucidate the molecular mechanisms of neurotransmitter secretion at the synapse. the molecules involved in transmitter release are likely targets for diseases that lead to neurologic and psychiatric disorders of athe nervous system. In addition, understanding biochemical pathway leading to transmitter release may some day allow the rational design of therapeutic compounds useful in treating diseases of the nervous system.